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Delay Discounting and Cannabinoid Enzyme Inhibitors Graduate Theses, Dissertations, and Problem Reports 2018 Delay Discounting and Cannabinoid Enzyme Inhibitors Devin Andrew Galdieri [email protected] Follow this and additional works at: https://researchrepository.wvu.edu/etd Part of the Experimental Analysis of Behavior Commons, Pharmacology Commons, and the Quantitative Psychology Commons Recommended Citation Galdieri, Devin Andrew, "Delay Discounting and Cannabinoid Enzyme Inhibitors" (2018). Graduate Theses, Dissertations, and Problem Reports. 3684. https://researchrepository.wvu.edu/etd/3684 This Thesis is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Thesis in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Thesis has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. Delay Discounting and Cannabinoid Enzyme Inhibitors Devin Andrew Galdieri Thesis submitted to the Eberly College at West Virginia University in partial fulfillment of the requirements for the degree of Master of Science in Psychology Karen G. Anderson, Ph.D., Chair Regina A. Carroll, Ph.D. Steven G. Kinsey, Ph.D. Department of Psychology Morgantown, West Virginia 2018 Keywords: Cannabinoid enzyme inhibitors, impulsive choice, impulsivity, delay discounting Copyright 2018 Devin Galdieri ABSTRACT Delay Discounting and Cannabinoid Enzyme Inhibitors Devin Andrew Galdieri Delay discounting is a measure of impulsive choice that is correlated with maladaptive behavior and psychological disorders. Disruptions to serotonin and dopamine pathways can cause changes in delay discounting, as can lesions to the prefrontal cortex and nucleus accumbens. The endocannabinoid system modulates other neurotransmitter systems, including dopamine and serotonin pathways. Cannabinoid receptors type 1 are found in relatively high concentrations in the nucleus accumbens and the prefrontal cortex. These receptors are activated by endogenous cannabinoids, which are synthesized on demand and broken down by catabolic enzymes. The action of these enzymes can be inhibited by a class of drugs known as cannabinoid enzyme inhibitors, which ultimately produce higher levels of endogenous cannabinoids by preventing their catabolic degradation. The present study examined effects of two cannabinoid enzyme inhibitors, URB597 and JZL195, on delay discounting in rats. Delay discounting was measured at baseline and after drug administration. Area under the curve and indifference points were not affected by any dose of either drug, but 7.5 mg/kg of JZL195 decreased percent larger-reinforcer choice at the lowest delay value and increased it at the highest delay value. URB597 increase percent larger-reinforcer choice only at one intermediate delay value. JZL195 increased response latencies at the 7.5 mg/kg dose. No systematic, dose-dependent effect of either drug on measures of delay discounting was observed. iii ACKNOWLEDGEMENTS I would like to thank Dr. Karen Anderson, Dr. Regina Carroll, and Dr. Steven Kinsey for their time, guidance and feedback as members of my thesis committee. I am sincerely grateful for all of the mentorship, training, and support that Dr. Karen Anderson, my advisor, has provided throughout my graduate career. I would like to express my gratitude to Dr. Steven Kinsey for his expert advice and guidance on the subject of cannabinoids and the endocannabinoid system. I would like to acknowledge the training that I have received from all of the excellent faculty at West Virginia University and I would also like to thank my colleagues Jenny Ozga-Hess and Matt Eckard for training me in the lab, helping me with experiments and lab work, and generally being wonderful lab-mates. Thank you, as well, to my mother and father, Janis Cross and Michael Galdieri, for their unconditional love and support. Last but not least, thank you to all of my friends in West Virginia, California, and everywhere else, for keeping me sane and motivated: Natalie Jones, Kristine Durkin, Ashlee Gresham, Jacob Solomon, Hannah Jones- Ozanian, Jesse Ozanian, Charles Curtis, and Edward Weaver. iv TABLE OF CONTENTS Page TITLE...............................................................................................................................................i ABSTRACT....................................................................................................................................ii ACKNOWLEDGEMENTS............................................................................................................iii TABLE OF CONTENTS................................................................................................................iv LIST OF FIGURES.........................................................................................................................v INTRODUCTION...........................................................................................................................1 METHOD......................................................................................................................................10 RESULTS......................................................................................................................................12 DISCUSSION ...............................................................................................................................20 REFERENCES .............................................................................................................................27 FIGURES. .....................................................................................................................................40 GLOSSARY..................................................................................................................................43 v LIST OF FIGURES Figure 1.......................................................................................................................................................40 Mean percentages of larger-reinforcer choice as a function of delay value for all rats when vehicle, URB597 or JZL195 were administered. Figure 2.......................................................................................................................................................41 Mean percentages of larger-reinforcer choice as a function of delay value for individual rats when vehicle or URB597 was administered. Figure 3.......................................................................................................................................................42 Mean percentages of larger-reinforcer choice as a function of delay value for individual rats when vehicle or JZL195 was administered. Running head: DELAY DISCOUNTING AND CANNABINOID ENZYME INHIBITORS 1 Delay Discounting and Cannabinoid Enzyme Inhibitors Delay discounting, a measure of impulsivity, has been implicated in a number of disorders and maladaptive behaviors including pathological gambling, substance abuse, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, personality disorders, suicidality, and psychopathology in general (Castellanos-Ryan et al., 2016; Dom, De Wilde, Hulstijn, Brink, & Sabbe, 2006; Heerey, Robinson, McMahon, & Gold 2007; Kirby, Petry, & Bickel, 1999; Rogers, Moeller, Swann, & Clark, 2010; Wiehler & Peters, 2015; Wilson, Mitchell, Musser, Schmitt, & Nigg, 2011). One facet of impulsivity is impulsive choice, which can be defined as the choice of a smaller, more immediate reinforcer over a larger, delayed reinforcer (Ainslie, 1974, 1975). Conversely, self-control has been defined as the choice of a larger delayed reinforcer over a relatively smaller immediate reinforcer (Rachlin & Green, 1972). The purpose of the present experiment was to assess effects of drugs that alter the endocannabinoid system using a procedure designed to measure impulsive choice. Delay- discounting procedures are commonly used to assess impulsive choice and there is experimental evidence that implicates serotonin (5-HT) and dopamine (DA), as well as the prefrontal cortex (PFC) and nucleus accumbens (NAc) in increased delay discounting (impulsive choice) (e.g., Bizot, Le Bihan, Puech, Hamon, & Thiébot, 1999; Cardinal, 2006; Evenden & Ryan, 1996; Winstanley, Theobald, Cardinal, & Robbins, 2004). The endocannabinoid system is an attractive target for research in general due to its therapeutic potential, and in terms of delay-discounting research, due to its effects on the neurotransmitter systems for 5-HT and DA and brain regions in the PFC and NAc (e.g., Lòpez-Moreno, González-Cuevas, Moreno, & Navarro, 2008; Reggio 2009). There are two main receptor types in the endocannabinoid system and two main endogenous compounds that activate them (Reggio, 2009). The different physiological and DELAY DISCOUNTING AND CANNABINOID ENZYME INHIBITORS 2 behavioral effects that follow activation of these different receptors and the neurotransmitters and brain regions affected by them provided rationale for choosing the drugs used in this study and those drugs’ likelihood of producing effects
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